The present invention relates to novel benzylidene derivatives, and an antirheumatic agent, an osteoclast formation inhibiting agent, a nitrogen monoxide production inhibiting agent, and a transcription factor NFxcexaB suppressing agent comprising said benzylidene derivative as an active ingredient. The present invention further relates to a method for the prevention and/or treatment of rheumatic diseases, a method for the inhibition of osteoclast formation, a method for the inhibition of nitrogen monoxide production, and a method for the suppression of transcription factor NFxcexaB.
Rheumatic disease is a systemic inflammatory disease involving a functional abnormality accompanied by swellings and pains in arthrosis as the primary symptom. The number of the patients in Japan is estimated as more than about 600 thousands (morbidity: about 0.5% of the Japanese population), and many of these patients are females of middle to advanced age. Although the development of this disease has not yet been well elucidated, it is believed to be a trigger for this disease that an immunological abnormality occurs for some reason, the autoimmune response is accelerated, and an activated macrophage, neutrophil, T-cell and the like are infiltrated to inflammatory focus. Then, these cells receive an inflammatory stimulus to produce various inflammatory mediators such as IL-1, IL-6, THF-xcex1, nitrogen monoxide (NO) and prostaglandin E2 (PGE2). The mediators then induce a cell adhesion factor, collagenase, protease and the like, which cause swelling and pain and accelerate the destruction of articular cartilage and bone.
According to the recent findings, activation of NFxcexaB due to inflammatory stimulation induces cyclooxygenase-2 (COX-2) and inductive nitrogen monoxide synthase (i-NOS), and also accelerates an expression of cytokines. Cytokines and NO produced in the inflammatory focus activate NFxcexaB.
As a result, it is believed that the production of inflammatory mediators is enhanced in the inflammatory focus and the chronic inflammation pathology accompanied by the tissue destruction is thus developed. NO is also associated with the activation of COX-2 and accelerates production of PGE2.
Certain benzylidene compounds exhibit an anti-inflammatory effect, and therefore, they are currently used the treatment of rheumatic diseases as a nonsteroidal anti-inflammatory drug (NSAID), for the purpose of suppressing pains and swellings. However, the use of such nonsteroidal anti-inflammatory drug is a mere symptomatic therapy for the suppression of pains and swellings due to rheumatic diseases and is not curable for the disease itself.
On the other hand, antirheumatic agents (disease-modifying antirheumatic drug) inhibit the progression of rheumatic pathology and they are used in a radical therapy for the disease. The compounds of the present invention have been found to inhibit articular bone destruction, a rheumatic pathology, in a rheumatic model animal (NZB/KN) to which a nonsteroidal anti-inflammatory drug is not effective. Thus, the compounds have been found to be effective in a radical therapy of rheumatic diseases via a different mechanism from that of anti-inflammatory agents.
Combination use of a disease-modifying antirheumatic drug (DMARD) such as immunosuppressants or immunomodulators and a nonsteroidal anti-inflammatory drug (NSAID) is often conducted in the treatment of chronic arthritis such as rheumatoid arthritis. However, these drug have drawbacks in that the former may often cause serious side effects such as blood disorder, and the latter may cause gastrointestinal disorder due to prolonged administration. Accordingly, a drug which possesses the DMARD and NSAID effects but less side effects would be very useful as a therapeutic agent for rheumatoid arthritis.
The present inventors have found that particular benzylidene derivatives, i.e. the compounds of formula I: 
wherein
R1 is hydrogen, lower alkyl, lower alkoxy, hydroxy lower alkyl, or carboxy lower alkyl and R4 is hydroxy; or
R1 and R4 taken together form xe2x80x94CR5R6xe2x80x94(CH2)mxe2x80x94Oxe2x80x94 or xe2x80x94CR5R6xe2x80x94(CH2)pCH(OH)xe2x80x94Oxe2x80x94
wherein m is an integer of 1 to 3;
p is an integer of 0 to 2; and
R5 and R6 are each independently hydrogen, lower alkyl, lower alkoxy, or hydroxy lower alkyl;
R2 is hydrogen, lower alkyl, lower alkoxy, hydroxy lower alkyl, or carboxy lower alkyl; and
R3 is hydrogen, lower alkyl, cycloalkyl, lower alkoxy, arylalkyloxy, heteroarylalkyloxy, lower alkylcarbonyl, arylcarbonyl, substituted or unsubstituted carbamoyl or the group represented by the formula:
xe2x80x94(CH2)nxe2x80x94Q
wherein Q is hydroxy, substituted or unsubstituted amino, aryl, heteroaryl, hydroxycarbonyl or lower alkyloxycarbonyl; and
n is an integer of 0 to 3
xe2x80x83exhibit not only anti-inflammatory effect but also antirheumatic effect. The present invention has been accomplished on the basis of the above finding.
The present inventors also have found that the above compounds inhibit enhanced formation of osteoclast caused by PGE2.
Also, the above compounds have been found to suppress an inducible nitrogen monoxide synthase (i-NOS) to inhibit NO production.
Further, the above compounds have been found to posses suppressive activity on a transcription factor NFxcexaB.
Accordingly, the present invention provides novel uses of such derivatives as an antirheumatic agent, an osteoclast formation inhibiting agent, a nitrogen monoxide production inhibiting agent, and a transcription factor NFxcexaB suppressing agent.
Thus, the present invention provides an antirheumatic agent comprising a compound of formula I or pharmaceutically acceptable salt or hydrate thereof as an active ingredient.
The present invention also provides an osteoclast formation inhibiting agent comprising a compound of formula I or pharmaceutically acceptable salt or hydrate thereof as an active ingredient.
The present invention further provides a nitrogen monoxide production inhibiting agent comprising a compound of formula I or pharmaceutically acceptable salt or hydrate thereof as an active ingredient.
The present invention yet further provides a transcription factor NFxcexaB suppressing agent comprising a compound of formula I or pharmaceutically acceptable salt or hydrate thereof as an active ingredient.
The compounds of the formula I wherein R1 and R2 are both t-butyl, more preferably R1 and R2 are both t-butyl and R4 is hydroxy, more preferably R1 and R2 are both t-butyl, R3 is lower alkyl and R4 is hydroxy, much more preferably R1 and R2 are both t-butyl, R3 is ethyl and R4 is hydroxy, are preferred antirheumatic agents, osteoclast formation inhibiting agents, nitrogen monoxide production inhibiting agents and transcription factor NFxcexaB suppressing agents.
The present invention further provides use of the compounds of formula I for the manufacture of anti-rheumatic agent.
Also, the present invention provides use of the compounds of formula I for the manufacture of osteoclast formation inhibiting agent.
Further, the present invention provides use of the compounds of formula I for the manufacture of nitrogen monoxide production inhibiting agent.
Yet further, the present invention provides use of the compounds of formula I for the manufacture of transcription factor NFxcexaB suppressing agent.
The present invention further provides a method for the prevention and/or treatment of rheumatoid arthritis which comprises administering an effective amount of a compound of formula I to mammals in need thereof.
Also, the present invention provides a method for the inhibition of osteoclast formation which comprises administering an effective amount of a compound of formula I to mammals in need thereof.
Further, the present invention provides a method for the inhibition of nitrogen monoxide production which comprises administering an effective amount of a compound of formula I to mammals in need thereof.
Yet further, the present invention provides a method for the suppression of transcription factor NFxcexaB which comprises administering an effective amount of a compound of formula I to mammals in need thereof.
Among the compounds represented by the above formula I, some compounds have been disclosed as inhibiting agent against PGE2 production in Japanese Patent Publication No. 211819/1994 (published on Aug. 2, 1994).
The present invention further provides novel compounds of formula Ixe2x80x2: 
wherein
R1xe2x80x2 is hydroxy lower alkyl or carboxy lower alkyl and R4xe2x80x2 is hydroxy; or
R1xe2x80x2 and R4xe2x80x2 taken together form xe2x80x94CR5R6xe2x80x94(CH2)mxe2x80x94Oxe2x80x94 or xe2x80x94CR5R6xe2x80x94(CH2)pCH(OH)xe2x80x94Oxe2x80x94
wherein m is an integer of 1 to 3;
p is an integer of 0 to 2; and
R5 and R6 are each independently hydrogen, lower
alkyl, lower alkoxy, or hydroxy lower alkyl;
R2xe2x80x2 is hydrogen, lower alkyl, lower alkoxy, hydroxy lower alkyl, or carboxy lower alkyl; and
R3xe2x80x2 is hydrogen, lower alkyl, cycloalkyl, lower alkoxy, arylalkyloxy, heteroarylalkyloxy, lower alkylcarbonyl, arylcarbonyl, substituted or unsubstituted carbamoyl or the group represented by the formula:
xe2x80x94(CH2)nxe2x80x94Q
wherein Q is hydroxy, substituted or unsubstituted amino, aryl, heteroaryl, hydroxycarbonyl or lower alkyloxycarbonyl; and
n is an integer of 0 to 3
or pharmaceutically acceptable salt or hydrate thereof.